Multiple cell types in the skeleton are known to express vascular endothelial growth factor-A (VEGFA or just VEGF). VEGF was initially identified as one of the key paracrine factors in both angiogenesis and vasculogenesis. Later, it became clear that it also has other important roles, including cellular survival during bone and cartilage development. In contrast to the paracrine functions of VEGF in vascular development and angiogenesis, the survival of endothelial cells, hematopoietic stem cells and tumor cells has been linked to intracrine/autocrine functions of VEGF. The different functions of VEGF during the development and maintenance of bone are still incompletely understood.
Multiple analyses of the conditional VEGF mutants have led to the conclusion that VEGF controls the balance between osteoblast and adipocyte differentiation in bone marrow mesenchymal stem cells (MSCs). The use of the transgene tdTomato as a fluorescent lineage marker reveals that the marrow adipocytes in the mutant mice are derived from Osterix-expressing progenitor cells. In vitro differentiation experiments using bone marrow mesenchymal stem cells demonstrate that the defects in osteoblastogenesis and adipogenesis resulting from the loss of VEGF can be rescued by retroviralmediated expression of VEGF but not by the addition of recombinant VEGF. This strongly suggests that the VEGF-mediated control of stem cell fate is regulated by intracellular but not paracrine VEGF. mesenchymal stem cells are known to express reduced levels of VEGF during aging, coinciding with the incidence of osteoporotic features, such as a loss in trabecular bone mass and an increase in marrow fat. This raises the possibility that age-dependent osteoporosis may be, in part, due to a progressive loss of VEGF-dependent mechanisms that stimulate osteoblast differentiation and repress the differentiation of adipocytes.
VEGF is a principal regulator of blood vessel formation and haematopoiesis, but the mechanisms by which VEGF differentially regulates these processes have been elusive. It is reported that VEGF controls survival of haematopoietic stem cells (HSCs) by a regulatory loop. A reduction in survival, colony formation and in vivo repopulation rates of haematopoietic stem cells can be observed after ablation of the VEGF gene in mice. Intracellularly acting small-molecule inhibitors of VEGF receptor (VEGFR) tyrosine kinase dramatically reduced colony formation of haematopoietic stem cells, thus mimicking deletion of the VEGF gene. However, blocking VEGF by administering a soluble VEGFR-1, which acts extracellularly, induced only minor effects. These findings support the involvement in haematopoietic stem cell survival of a VEGF-dependent internal autocrine loop mechanism (that is, the mechanism is resistant to inhibitors that fail to penetrate the intracellular compartment). Not only ligands selective for VEGF and VEGFR-2 but also VEGFR-1 agonists rescued survival and repopulation of VEGF-deficient haematopoietic stem cells, revealing a function for VEGFR-1 signalling during haematopoiesis.
VEGF/KDR signaling affects the fate of neuronal stem cells derived from the embryonic brain. On the one hand, VEGF promotes the survival of definitive neural stem cells, which form in the developing brain after 8.5 dpc and persist throughout adulthood. On the other hand, VEGF inhibits the survival of primitive neural stem cells, present in the embryonic brain up to 8.5 dpc. Interestingly, primitive neural stem cells would not normally be exposed to high VEGF levels until after 8.5 dpc, when VEGF is upregulated in the neural tube to attract blood vessels from the perineural vascular plexus. These observations raise the possibility that VEGF contributes to a developmental switch that affects neural stem cell behavior. KDR expression has also been reported in the proliferative zones of the adult rodent brain, although the specificity of the antibodies used was demonstrated in only one of these studies. When VEGF is administered to the brain at low concentrations, it stimulates the proliferation of KDR-expressing cells in the ventricular zone in vivo independently of its effect on blood vessels. VEGF application was also found to promote the survival of neural stem cells in vitro in a KDR-dependent fashion. The physiological significance of VEGF as an autocrine or paracrine signal for neuronal stem cells is not yet understood, as it has not been possible to ablate VEGF expression in the CNS without simultaneously affecting blood vessels. The specific deletion of VEGF receptors in the early neuronal lineage may therefore provide a more suitable approach to determine the contribution of VEGF signaling to eurogenesis. The ablation of KDR expression from neurons using nestin promoter-driven CRE-mediated recombination suggested that this VEGF receptor is not essential for embryonic neurogenesis. However, the impact of KDR loss from CNS neurons on neonatal and adult neurogenesis or neuronal survival has not yet been studied, and FLT1 and NRP1 have not yet been ablated specifically in the neuronal lineage. Further work on the role of VEGF and its receptors in the neuronal lineage has become pressing, given that reduced VEGF levels were found to cause motor neuron degeneration.
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• Rosenstein J M, Krum J M, Ruhrberg C. VEGF in the nervous system[J]. Organogenesis, 2010, 6(2): 107-114.